Stable Angina

OBJECTIVE
To describe the epidemiology, impact, pathogenesis, patient presentation, and treatment of stable angina, including the use of vasculoprotective and antianginal drug therapies and coronary revascularization procedures.


SUMMARY
Stable angina is an age-related condition that typically affects men at an earlier age than women, adversely affects quality of life, and increases mortality. Stable angina is the result of an increase in myocardial oxygen demand in the setting of coronary arteries chronically narrowed by large, stable atherosclerotic plaques and a diminished myocardial oxygen supply. The characteristics of the chest pain or discomfort contribute to the clinical presentation. Treatment guidelines call for efforts to modify CHD risk, antianginal drug therapy, and patient education. Angiotensin-converting enzyme inhibitors and low-dose aspirin or clopidogrel may be used to reduce the risk of myocardial infarction and death. A beta-blocker or a nondihydropyridine calcium channel blocker may be used as initial antianginal drug therapy, and a long-acting nitrate or dihydropyridine calcium channel blocker may be added. The choice among antianginal drug therapies often hinges on patient characteristics, contraindications, and adverse effects. Revascularization with percutaneous coronary intervention or coronary artery bypass graft surgery is an option for ischemia refractory to maximum tolerated dosages of antianginal therapy.


CONCLUSION
Various drug therapies may be used to manage stable angina, with coronary revascularization as an option in patients who are refractory to drug therapy. However, antianginal drug therapies may prove inadequate for managing anginal episodes for a variety of reasons, and revascularization is not always effective.

S table angina is one of several possible manifestations of coronary artery disease (CAD), a common, deadly, and costly disease in the United States (see the Introduction to this supplement). CAD and other cardiovascular diseases are agerelated conditions (Figure 1). 1 While CAD is the leading cause of death for both women and men, women usually develop CAD about 10 years later than men, and they experience myocardial infarction (MI), sudden death, and other serious sequellae roughly 20 years after men. 1 The initial manifestation of CAD usually is angina in women and MI in men. 2 Among patients with CAD, the total number of patients with chronic stable angina is difficult to determine. Chronic stable angina is the initial manifestation of ischemic heart disease in approximately half of patients. 3,4 Using these numbers, along with estimates based on patients surviving MI, it is predicted that between 6 and 12 million Americans have chronic stable angina. The risk of mortality is greatest for white men, followed by white women, black men, and black women. 5 ss Impact Angina has a substantial impact on mortality and quality of life. Angina episodes typically are triggered by exertion or emotional stress, so the physical activities of patients with stable angina are limited. 6 In a prospective study of 8,908 Veterans Affairs outpatients with CAD who were followed for an average of 2 years, the risk of death increased progressively with the self-reported degree of physical limitation due to angina. 7 The average age of participants was 67 years, 98% were male, 66% were white, and 25% had diabetes mellitus (DM). There were 896 deaths. A high degree of physical limitation increased the risk of death 2.5 times compared with little or no physical limitation, a difference that is significant. The degree of physical limitation may reflect the extent of atherosclerosis, which narrows the coronary arteries and reduces the blood and oxygen supply to the myocardium.
The patient characteristics, frequency of angina attacks, and impact of angina on perceived well-being were assessed in 5,125 outpatients with chronic stable angina living in a variety of geographic areas. 8 The average patient age was 69 years, 53% of patients were women, 70% had more than 1 associated illness, and 64% received more than 1 cardiovascular drug. The median frequency of angina was approximately twice weekly. Ninety percent of patients experienced angina during activity, and 47% also had angina at rest. The frequency of angina was significantly correlated with patients' perception of their overall well-being, with poorer health associated with higher frequencies of angina.

ss Pathogenesis
Angina is the result of myocardial ischemia, which is due to an imbalance between myocardial oxygen supply and demand. In a healthy person, the myocardial blood flow and oxygen supply increase in response to increases in oxygen demand during physical exertion through various humoral, neural, and metabolic mechanisms that regulate vascular resistance and coronary blood flow. 2 Angina episodes in patients with chronic stable angina are typically precipitated by an increase in myocardial oxygen demand (MVO 2 ) in the setting of a fixed decrease in supply. The major determinates of MVO 2 include heart rate, myocardial contractility, and intramyocardial wall tension. Intramyocardial wall tension is the leading contributor to increased MVO 2 and is directly related to the radius or size of the ventricular cavity and blood pressure, but indirectly related to the ventricular muscle mass. The rate of increase of MVO 2 can be as important as the total amount of MVO 2 . The rate-pressure product, or double product, is a common noninvasive measure of MVO 2 , which is the product of the heart rate and systolic blood pressure (SBP). However, any change in contractility or volume loading of the left ventricle (LV) is not considered by the double product.
The etiology of the fixed decrease in supply is long-standing, well-developed atherosclerotic plaques. Coronary plaques that contribute to exertional angina symptoms usually obstruct ≥70% of the epicardial coronary vessel lumen. 2 The reduction in supply is a result of obstruction of coronary blood flow by a large plaque compared with a ruptured plaque as in an acute coronary syndrome. The plaques in chronic stable angina patients are more stable, have a reduced lipid pool, and rupture infrequently. Since their geometry does not typically change acutely, they provide a relatively fixed decrease in myocardial oxygen supply.
The plaques provide a resistance to coronary blood flow in the epicardial vessels that generally do not offer any resistance to flow in patients without disease. Increases in MVO 2 are met by vasodilation of endocardial vessels that feed the myocytes. In patients with a fixed coronary lesion in the epicardial vessels, the endocardial vessels must dilate to provide adequate oxygen and blood supply to the myocytes at rest. During periods of increased MVO 2 in these patients, the endocardial vessels are already maximally vasodilated and, therefore, can provide no additional myocardial oxygen supply. The increased MVO 2 can come from increased physical activity or emotional stress. Since the increased MVO 2 demand cannot be satisfied due to the fixed reduction in supply, and maximal endocardial vasodilation at rest, angina is precipitated.

ss Patient Presentation
The diagnosis of stable angina involves a detailed history to characterize the nature, timing, and location of chest discomfort; precipitating factors; and the response to palliative measures (i.e., nitroglycerin or rest). 2,9 The PQRST mnemonic (Precipitating factors and Palliative measures, Quality of pain, Region and Radiation of pain, Severity of pain, Temporal factors) often is used by clinicians to evaluate chest pain and help rule in or out a cardiac cause. Other elements of a diagnostic work-up for a patient with suspected angina and CAD should include a physical examination, history of risk factors for CAD (cigarette smoking, dyslipidemia, hypertension, DM, and family history of premature CAD), electrocardiography, chest X-ray, and possibly an echocardiography, radionuclide imaging studies, and/or coronary angiography. 9 The typical complaints of a patient with chronic stable angina includes chest pain that is precipitated by exertion, such as walking, gardening, house cleaning, or sexual activity. Upon exertion, MVO2 has exceeded what can be provided by the fixed decrease in supply from the occlusive atherosclerotic plaque. The chest pain is typically relieved by rest or sublingual nitroglycerin (SL NTG). The quality of angina chest pain is often described as squeezing, crushing, a heaviness, or tightness in the chest. It can also be more vague and described as a numbness or burning in the chest. Chest pain that is described as sharp in origin, pain that increases with inspiration or expiration, or a reproducible pain with palpation is usually not cardiac pain. The region of the pain is substernal and may radiate to the right or left shoulder, right or left arm (left more commonly than right), neck, back, or abdomen. The severity of cardiac chest pain can be difficult to quantify since pain is a subjective measure, but the pain is usually considered severe and ranked a 5 or higher on a 10-point scale. It is important to remember that women and the elderly may present with atypical chest pain, and patients with DM may have a decreased sensation of pain due to complications of neuropathy. By definition, the timing or duration of the chest pain in patients with chronic stable angina is less than 20 minutes, but is usually around 5 to 10 minutes. A variety of noncardiac causes of chest pain must also be considered, such as gastroesophageal reflux, esophageal motility disorders, biliary colic, costosternal syndrome, or musculoskeletal disorders. 2,9 The most recent guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) for www.amcp.org Vol. 12

Ages (Years)
managing patients with chronic stable angina were released in 2002. 9 Important advances have been made since then, but the guidelines remain relevant. According to the ACC/AHA guidelines, the goal of treatment in most patients with stable angina is the complete or nearly complete elimination of chest pain and a return to normal activities with minimal adverse effects, although the goal for an individual depends on his or her clinical characteristics and preferences. 9 Prevention of MI and death is another therapeutic objective in this patient population. A 3-pronged approach to treatment is outlined in the guidelines, including modification of CAD risk, antianginal therapy, and patient education about the risk factors, pathophysiology, complications, and treatment of CAD. 9 Despite the fact that the patient with chronic stable angina has already developed CAD, risk-factor reduction and management are important to prevent progression of atherosclerotic disease.
Smoking cessation and lifestyle modification (i.e., diet, exercise, weight reduction if overweight) for patients with dyslipidemia or hypertension also are recommended to reduce CAD risk. Antilipemic and antihypertensive drug therapy in accordance with guidelines of the National Cholesterol Education Program' s Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults and the Joint National Committee for Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, respectively, may be required. 10,11 Management of DM through lifestyle modification and, if needed, antidiabetic drug therapy, is advised because DM is considered a CAD risk equivalent. 10 Low-dose aspirin (81 mg/day) is recommended, with clopidogrel as an alternative for patients with contraindications to aspirin. 9 The antithrombotic effect of aspirin and clopidogrel reduces the risk of MI and death. 9 ss Antianginal Drug Therapy The antiangina drug therapies used in patients with stable angina provide their benefit by mainly reducing the different components of MVO 2 (Table 1). Some agents may also provide some coronary vasodilation and increased myocardial oxygen supply, but this is not the primary method of benefit, and results are not consistent between agents. Aspirin, clopidogrel, and angiotensin-converting enzyme (ACE) inhibitors are vasculoprotective therapies that reduce the risk of MI and death in patients with stable angina. 9 All patients with chronic stable angina should have access to SL NTG tablets or spray as recommended in the ACC/AHA guidelines. 9 Regardless of whether the patient is utilizing medical management, revascularization, or a combination of approaches, patients need treatment for acute attacks of angina. About 75% of all exertional angina episodes will be relieved with the first SL NTG dose with another 10% to 15% of patients achieving relief with the next 2 doses. 12 The tablets also may be used prophylactically before situations likely to provoke angina such as exercise. 12 Clearly the major contributing factor to successful use of SL NTG is appropriate patient education from the pharmacist. If patients do not receive appropriate patient counseling on the use and storage of this agent, the opportunities for successful utilization are greatly reduced. 13 Beta-blockers are commonly used in the management of patients with chronic stable angina. By reducing heart rate, myocardial contractility, and intramyocardial wall tension (Table 1), beta-blockers impact all of the major contributing factors of MVO 2 . Heart-rate reduction may also improve myocardial oxygen delivery by prolonging diastole and increasing the time for myocardial perfusion. Beta-selectivity does not impact the efficacy of beta-blockers in the treatment of chronic stable angina, and all agents appear equally effective. Beta 1-selective agents would be preferred in patients with chronic obstructive pulmonary disease (COPD), peripheral vascular disease, DM, dyslipidemias, and sexual dysfunction. 9 Calcium channel blockers (CCBs) are also effective in reducing angina episodes in patients with chronic stable angina. Like betablockers, nondihydropyridine (NDHP) CCBs reduce all of the components of MVO 2 ( Table 1). The similarity in pharmacodynamic effects of beta-blockers and NDHP CCBs suggests that either drug class might be used as initial antianginal therapy in patients with stable angina. All dihydropyridine (DHP) CCBs provide blood pressure reduction and, therefore, a reduction in intramyocardial wall tension. However, there is variation between the DHP CCBs in their impact on contractility and development of reflex tachycardia. Both DHP and NDHP CCBs provide some increase in myocardial blood flow. This increase in flow is due to the ability of the CCBs to decrease the cellular uptake of calcium and dilate epicardial coronary arteries. Most studies comparing beta-blockers and CCBs in patients with stable angina focused on the impact on the number and duration of angina episodes or the increase in exercise time to 1-mm ST segment depression. 9 Few studies have compared the impact of these drug therapies on cardiovascular outcomes or mortality in patients with stable angina.
Calcium channel blockers and beta-blockers are equivalent in efficacy for relieving angina and increasing exercise time, although Impact of Antianginal Drug Therapies on Myocardial Oxygen Demand 2,9,12  some studies suggest that beta-blockers are more effective than DHP CCBs. 9 In a randomized double-blind, parallel-group study of 330 patients with chronic stable angina, both the beta-blocker bisoprolol and the DHP CCB nifedipine reduced the number (8.1 episodes/48 hours to 3.2 episodes/48 hours for bisoprolol and 8.3 epidoses/48 hours to 5.9 episodes/48 hours for nifedipine) and duration of angina episodes (99.3 minutes/48 hours to 31.9 minutes/48 hours for bisoprolol and 101 minutes/48 hours to 72.6 minutes/48 hours for nifedipine). While both groups demonstrated a significant benefit over baseline, bisoprolol was significantly more effective than nifedipine for both outcomes (P <0.001). 14 In a randomized, double-blind, placebo-controlled study of 280 patients with stable angina, the beta-blocker metoprolol and nifedipine both increased exercise time (66 seconds metoprolol and 43 seconds for nifedipine; P <0.01 for both compared with baseline), although metoprolol was more effective than nifedipine (P <0.05). 15 These findings suggest that an NDHP may be a better choice than a DHP for patients with stable angina if a CCB is chosen. In a randomized, double-blind, parallel-group study of the beta-blocker atenolol, the DHP CCB nifedipine, and a combination of these 2 drugs in 682 patients with chronic stable angina, there was a nonsignificant trend toward a lower incidence of cardiac death, nonfatal MI, and unstable angina with combination therapy compared with monotherapy (12.8% atenolol, 11.2% nifedipine, and 8.5% combination therapy; P = 0.14), and there was no significant difference between atenolol and nifedipine. 16 In 809 patients with chronic stable angina, there were no significant differences between metoprolol and the NDHP CCB verapamil in mortality (5.4% metoprolol vs. 6.2% verapamil; P = NS [not significant]) or quality of life. 17 These findings suggest that cardiovascular outcomes and mortality are similar regardless of whether a beta-blocker or CCB is used as initial antianginal therapy in patients with stable angina.
According to ACC/AHA guidelines, a beta-blocker should be used as initial antianginal drug therapy in patients with stable angina in the absence of contraindications to beta-blocker use. 9 The guidelines call for the addition or substitution of an NDHP CCB if beta-blockers are contraindicated, cause unacceptable adverse effects, or are ineffective in controlling angina episodes. The ACC/AHA recommendation for use of beta-blockers as initial antianginal therapy in patients with stable angina is based largely on robust evidence of a survival benefit from beta-blocker therapy in other patient populations that often develop stable angina (e.g., patients with a recent MI or hypertension). 9 The choice between a beta-blocker and CCB for an individual with stable angina probably will hinge on patient characteristics and the contraindications and adverse effects associated with the drugs ( Table 2). For example, a beta-blocker is appropriate for a patient with a recent MI, but an NDHP CCB may be preferred for a patient with COPD and no history of MI.
The choice of add-on therapy for a patient with inadequate control of angina episodes from a beta-blocker may depend on whether the patient has continued hypertension. A long-acting nitrate may be added if hypertension is absent, or a DHP CCB could be added if hypertension is present. Tachycardia associated with nitrates or DHP CCBs is attenuated by beta-blockers and NDHP CCBs. 9 Long-acting nitrates (e.g., nitroglycerin ointment and transdermal patches, isosorbide dinitrate, and isosorbide mononitrate extended-release tablets) dilate coronary arteries, which increase myocardial oxygen supply, and they decrease intramyocardial wall tension and MVO 2 , although they may cause reflex tachycardia. 12 Long-acting nitrates increase exercise tolerance and prevent or delay the onset of angina. 12 Long-acting nitrates should not be used as monotherapy in patients with stable angina because a 10-to 14-hour nitrate-free interval is needed on a daily basis to prevent the development of tolerance, which limits the efficacy of such therapy. 12,13 The use of another antianginal agent in combination with the longacting nitrate is needed to provide protection from ischemia during this nitrate-free interval. Ideally, a long-acting nitrate is added to a beta-blocker or NDHP CCB in a patient whose heart rate is at or near the goal of 55 to 60 beats per minute at rest. Long-acting nitrates also are beneficial for patients with heart failure. 12 www.amcp.org Vol. 12

Contraindications to Use of and Adverse
Effects From Antianginal Drugs 2,9,12  ss Refractory Ischemia Current antiangina drug therapy options may prove inadequate for managing anginal episodes for a variety of reasons. A patient may have contraindications to the use of one or more drugs or be unable to tolerate initial or larger, therapeutic dosages. Additive hemodynamic effects from combination therapy (e.g., the blood pressure-lowering effects of beta-blockers and CCBs) may cause problems before angina relief is achieved. Angina may persist despite the use of combination antiangina therapy at maximum tolerated dosages, even with careful monitoring of blood pressure and heart rate. Patients may be dissatisfied with therapy despite a measurable improvement in exercise tolerance and/or reduced number of episodes. Patients' perceptions of what to expect from therapy and what is delivered can vary widely. Surgical revascularization plays an important and growing role in the treatment of chronic stable angina. Revascularization options usually consist of coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) with or without stent placement. Other options are available and under development, but they are less established. The goal with revascularization is to prolong life and eliminate or reduce symptoms. 9 Whereas most of the pharmacologic approaches reduce MVO 2 , revascularization increases myocardial oxygen supply in vessels with critical stenosis. This is accomplished by opening the vessel via PCI with or without stent placement or using alternative transplanted vessels to bypass a critical stenosis in the setting of CABG surgery. While both of these therapies provide significant improvement in the care of patients with chronic stable angina and have advantages in certain groups of patients over a pharmacologic approach, both revascularization treatments have limitations.
PCI involves insertion of a catheter with a deflated balloon at the tip into the femoral artery in the groin area and threading of the catheter through the aorta into a coronary artery narrowed by an atherosclerotic plaque. 18 Inflation of the balloon compresses the plaque, restoring patency to the vessel. In most cases, a drug-eluting intracoronary stent is inserted in the reopened vessel to prevent restenosis and reduce the need for repeat revascularization. 1 In CABG surgery, a segment of the saphenous vein or the internal mammary artery is grafted onto the coronary vasculature to circumvent an occluded coronary artery and restore perfusion to an area of the myocardium with an inadequate blood supply. 9 New approaches to CABG surgery have been developed in an attempt to minimize the morbidity related to the operation. One of these approaches is the off-pump bypass coronary surgery that is performed on a beating heart. Patients undergoing off-pump bypass experience the same relief from angina, vessel patency, and mortality benefit (evaluated out to 1 year) as traditional CABG surgery. 19 Patients utilizing off-pump bypass with sternotomy can undergo multivessel bypass, but data on patients with left main disease and impaired LV function are limited. By reducing the need for cardiopulmonary bypass and preventing the need for clamping of the aorta, there is a significant reduction in adverse neurologic events, length of hospitalization, and cost. 19 Revascularization does not always eliminate angina episodes or the need for antianginal medications. In 1,205 patients with multivessel disease who underwent PCI or CABG in the hope of achieving angina relief, approximately 10% to 20% continued to experience angina and roughly 60% to 80% required antianginal medication 1 year after the procedure. 20 In another group of 1,755 patients who underwent PCI for angina symptoms or acute MI, angina persisted 1 year after the intervention in 26% of patients. 21 ss Role of ACE Inhibitors ACE inhibitors have no effect on angina, but they may reduce the risk of MI and death in patients with stable angina. 9 The results of studies of the use of ACE inhibitors in patients with CAD are somewhat controversial. Several, but not all, studies demonstrated a reduction in morbidity and mortality, especially in patients with heart failure, DM, or a previous MI. 9, 21-24 Therefore, ACE inhibitors have a role in the management of stable angina despite their lack of an impact on angina episodes. However, the use of ACE inhibitors may be limited by hypotension from antianginal drug therapies or may limit the ability to use certain antianginal drug therapies for the same reason.

ss Conclusion
Patients with chronic stable angina make up a significant portion of patients with CAD. The goals of therapy in these patients consist of reducing angina symptoms and prolonging life. Current medical therapy with the use of beta-blockers, CCBs, and nitrates has been shown to improve angina symptoms, but not reduce mortality. Proper patient evaluation and screening will aid in appropriate antianginal medication selection for each individual. When used in appropriate situations, revascularization can improve angina control compared with medical therapy alone. Regardless if a medical and/or revascularization approach is utilized, patients require aggressive risk-factor reduction against smoking, hypertension, and hyperlipidemia. The pharmacist must play a key role in not only recommending and monitoring the prescribed therapy but also in educating patients.

DISCLOSURES
This article is based on a presentation given by the author at a symposium titled "Emerging Therapies for Management of Patients with Stable Angina: Focus on Clinical Efficacy and Outcomes" at the Academy of Managed Care Pharmacy' s 18th Annual Meeting and Showcase in Seattle, Washington, on April 5, 2006. The symposium was supported through an educational grant from CV Therapeutics, Inc. The author received an honorarium from CV Therapeutics, Inc. for participation in the symposium. He discloses no potential bias or conflict of interest relating to this article.